The present invention relates to compositions and methods for promoting weight loss and/or preventing weight gain in mammals by administering phytochemicals. Among the phytochemicals useful in the compositions and methods of the invention are dietary indole, Diindolylmethane (DIM), as well as its precursor, Indole-3-carbinol (I3C), and cogener, 2-(Indol-3-ylmethyl)-3,3xe2x80x2-diindolylmethane (LTR-1). When used as described, these natural substances, alone and in combination with other substances, facilitate weight loss as part of a nutritional system targeting release and metabolism of stored fat.
The term xe2x80x9coverweightxe2x80x9d describes an excessive accumulation of body fat or xe2x80x9cadiposityxe2x80x9d. xe2x80x9cOverweightxe2x80x9d is defined as an elevation in the Body Mass Index (BMI) beyond desirable standards due to increased body fat. The BMI expresses an individual""s degree of overweight independent of height by dividing weight in kilograms (Kg) by height squared (m2). In overweight men a BMI above 25 Kg/m2 and in overweight women a BMI above 26 Kg/m2 defines a level of adiposity which negatively impacts health (Simopoulos, A.P., Body Weight Reference Standards, In Van Itallie, T.B. and Simopoulos, A.P. (Eds), Obesity: New Directions in Assessment and Management, The Charles Press, Inc., Philadelphia, Pa., 1995). The increasing prevalence of overweight is one of the major health problems of industrialized countries. Overweight occurs as a result of an imbalance between energy intake as food and energy expenditure through physical activity. Most importantly, the trend to increased consumption of sugar and refined carbohydrate in excess of energy needs results in a metabolic and hormonal status favoring the formation and storage of fat. Weight loss depends on mobilization and metabolism of fat at the cellular level. This requires the metabolic process of lipolysis and encompasses the release of stored fat from fat cells. In all mammals the process and rate of lipolysis are highly regulated by the system of catecholamine hormones.
Increased carbohydrate consumption in modern society is the result of the introduction of refined sugar and processed carbohydrate in various forms. The addition of high fructose corn syrup in 1967 is a prime example of this shift in dietary composition which has contributed to the further increase of the sugar component of the average diet to about 8% of total calories (Raper, N., and Marston, R., xe2x80x9cContent of the U.S. food supply (tables of nutrients and foods)xe2x80x9d, Human Nutrition Information Service: Washington, D.C., U.S. Department of Agriculture, 1988). The presence of sugar and other xe2x80x9chigh glycemicxe2x80x9d processed carbohydrates found in bread and pasta, increases blood insulin levels, inhibits lipolysis, and promotes new fat synthesis. This raises serum triglycerides, serum cholesterol, and increases the risk of atherosclerosis and coronary heart disease. Strategies to decrease our daily intake of processed carbohydrate and increase the release and metabolism of stored fat are clearly needed.
Interventions to decrease appetite have focused on supporting brain levels of the neurotransmitter serotonin which is derived from the amino acid tryptophan. However, simply providing increased dietary sources of tryptophan have in themselves not proven successful at reducing appetite. Use of drugs such as fluoxetine and fenfluramine, which raise brain serotonin levels, have proven effective in promoting weight loss. Unfortunately, this pharmacologic approach has been recently associated with serious cardiovascular side effects (Kolanowski, J., xe2x80x9cA risk-benefit assessment of anti-obeisity drugsxe2x80x9d, Drug Safety 20(2):119-131, 1999). Use of the serotonin precursor, L-5-hydroxy-tryptophan (5HTP) may represent a safer approach to reducing appetite for carbohydrates. Other safe and effective means to promote weight loss are clearly needed.
With regard to increasing fat metabolism, both caloric restricted dieting and increased exercise promote a more active catecholamine system which favors active lipolysis. Increasing the efficiency of this process has been the object of much of the pharmacotherapy of obesity.
The process of lipolysis is regulated primarily by the system of catecholamine hormone receptors present on the surface of fat cells. These catecholamine receptors consist of a family of membrane bound proteins with differerent structure and activity known as the xcex1 and xcex2 receptors. The xcex1 and xcex2 receptors have opposing action on the rate of lipolysis. Predominance of activity from the xcex2 receptors favors active lipolysis and translates into weight loss. Predominance of xcex1 receptor activity inhibits lipolysis and favors continued fat storage. Nature has provided for an adaptive mechanism by which activity and number of the a receptors increase with caloric restriction. This slows continued lipolysis during periods of fasting and results in the increased loss of muscle tissue in addition to fat during dieting. The increased presence and activity of xcex1 receptors and decreased overall metabolic rate which occur during fasting has been call the xe2x80x9cstarvation responsexe2x80x9d. The starvation response reduces the efficiency of lipolysis during weight loss.
Much of modern obesity research has concerned methods for maintaining a hormonal balance which favors xcex2 over xcex1 receptor activity to promote more efficient and active lipolysis. The objective is to facilitate continued lipolysis or fat loss while preserving muscle or xe2x80x9clean body massxe2x80x9d. This is achieved with exercise, a restricted calorie but protein supplemented diet, and with the administration of substances which mimic the xcex2 receptor activity of the catecholamine hormones. The most popular xcex2 stimulating substance in use since antiquity is ephedrine, originally discovered in the Chinese herb xe2x80x9cMa Huongxe2x80x9d. Ephedrine resembles the catecholamine hormone, epinephrine, and effectively increases the rate of lipolysis. However, like epinephrine, ephedrine produces serious side effects related to overstimulation of the sympathetic nervous system, including tachycardia, hypertension, nervousness, tremor and insomnia (Cupp, M. J., xe2x80x9cHerbal remedies: adverse effects and drug interactionsxe2x80x9d, American Family Physician 59(5):1239-45, 1999). To offer alternatives to the use of ephedrine and related drugs like amphetamines, the pharmaceutical industry has attempted with little success to develop xcex2 receptor stimulants with more specific action limited to the promotion of lipolysis in fat cells.
Another attractive approach, to increasing rates of lipolysis has been blockade of the catecholamine xcex1 receptor system Lafontan, M., Berlan, M., et al., xe2x80x9cAlpha-2-adrenoceptors in lipolysis: xcex12 antagonists and lipid mobilizing strategiesxe2x80x9d, Am. J. Clinical Nutrition 55:219S-227S, 1992). This has been possible with oral use of yohimbine, another natural compound which blocks xcex1 receptors allowing the epinephrine and norepinephrine already present to have unopposed action at the xcex2 receptors. While theoretically an attractive approach, and successful in promoting weight loss in dogs (Berlan, M., Galittzky, J., et al., xe2x80x9cAnorectic effect of alpha2-antagonists in Dog: effect of acute and chronic treatmentxe2x80x9d, Pharmacology Biochemistry and Behavior 39:313-320, 1991), the use of yohimbine has only inconsistently promoted increased weight loss in placebo controlled studies in humans (Sax, L., xe2x80x9cYohimbine does not affect fat distribution in menxe2x80x9d, International Journal of Obesity 15:561-565, 1991, and Berlin, I., Stalla-Bourdillon, A., et al., xe2x80x9cLack of efficacy of yohimbine in the treatment of obesityxe2x80x9d, J. of Pharmarmocologie (Paris) 3:343-347, 1986).
The need thus remains to develop other approaches and applications of safe natural substances to effectively promote lipolysis and facilitate weight loss.
Diindolylmethane (DIM), as well as its precursor, Indole-3-carbinol (I3C), and cogener, 2-(Indol-3-ylmethyl)-3,3xe2x80x2-diindolylmethane (LTR-1) are natural phytochemicals and part of the family of dietary indoles discovered in cruciferous vegetables. DIM and I3C are found in all cruciferous vegetables including broccoli, cauliflower, cabbage and Brussels sprouts (Bradfield C A and Bjeldanes L F, High performance liquid chromatographic analysis of anticarcinogenic indoles in Brassica oleracea, J Agric. Food Chem., 1987, 35:46-49). DIM, together with the linear trimer, LTR-1, are formed from the precursor indole, I3C, after the enzymatic release of I3C from parent glucosinolates found in all cruciferous vegetables. Supplemental use of DIM and I3C are effective in humans in adjusting the pathways of estrogen metabolism to favor the production of 2-hydroxy estrogen metabolites (Michnovicz, J J, et al., Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans, J Natl Cancer Inst., 1997 May 21, 89(10):718-23). An increased proportion of 2-hydroxy metabolites is correlated to protection from breast cancer. This relationship has been documented in case-control studies (Ho GH, et al. Urinary 2/16 xcex1-hydroxyestrone ratio: correlation with serum insulin-like growth factor binding protein-3 and a potential biomarker of breast cancer risk, Ann Acad Med Singapore, 1998, 27:294-299, and Schneider, J., et al., Abnormal oxidative metabolism of estradiol in women with breast cancer, Proc Natl Acad Sci USA, 1982, 79:3047-3051). The use of I3C, which converts to DIM and LTR-1 after passage through the stomach, has been the subject of a U.S. Pat. No. 5,895,787 describing the use of I3C and related dietary indoles to reduce the symptoms of fibromyalgia. Use of DIM and LTR-1 in absorption enhancing formulations for improving the balance of estrogen metabolites has been the subject of earlier investigations and provides the basis of U.S. Pat. No. 6,086,915. No prior investigations have suggested that DIM, I3C or LTR-1 might be potentially useful agents to promote lipolysis or facilitate weight loss.
The present invention provides methods and compositions for the promotion of weight loss and the maintenance of body weight. In particular, the present invention relates to the administration of phytochemicals, preferably I3C, DIM and/or LTR-1, for the promotion of weight loss and the maintenance of body weight by preventing weight gain. In a preferred embodiment, the dietary indole is xe2x80x9cprocessedxe2x80x9d, referring to a dietary indole that has been processed according to the methods described in U.S. patent application Ser. No. 09/053,180.
Also according to the present invention, a pharmaceutical composition is provided, which comprises a phytochemical, preferably I3C, DIM and/or LTR-1, and, optionally, pharmaceutically acceptable carriers.